The Added Value of MRI-Based Targeted Biopsy in Biopsy-Naïve Patients: A Propensity-Score Matched Comparison.

BACKGROUND: Multiparametric Magnetic Resonance Imaging (mpMRI)-based targeted biopsy has shown to be beneficial in detecting Clinically Significant Prostate Cancer (csPCa) and avoiding diagnosis of Non-csPCa (ncsPCa); however, its role in the treatment of biopsy-naïve patients is still under discussion. METHODS: After identifying predictors for the diagnosis of csPCa via Multivariate Logistic Regression Analysis (MLRA), a propensity-score (1:1 nearest neighbor) matched comparison was performed between a Systematic-Only Biopsy (SOB) cohort and a mpMRI-based Combined (systematic + targeted) Biopsy (CB) cohort from two tertiary urologic centers (SOB: Department of Urology, University General Hospital of Heraklion, University of Crete, School of Medicine, Heraklion, Crete, Greece; CB: LKH Hall in Tirol, Austria). Only biopsy-naïve patients were included in the study. The study period for the included patients was from February 2018 to July 2023 for the SOB group and from July 2017 to June 2023 for the CB group. The primary outcome was the diagnosis of csPCa (≥ISUP 2); secondary outcomes were overall cancer detection, the added value of targeted biopsy in csPCa detection, and the reduction in ncsPCa diagnosis with CB compared to SOB. To estimate the Average Treatment effect of the Treated groups (ATT), cluster-robust standard errors were used to perform g-computation in the matched sample. p-values < 0.05 with a two-sided 95% confidence interval were considered statistically significant. RESULTS: Matching achieved well-balanced groups (each n = 140 for CB and SOB). In the CB group, 65/140 (46.4%) patients were diagnosed with csPCa compared to 44/140 (31.4%) in the SOB group (RR 1.48, 95%-CI: 1.09-2.0, p = 0.01). In the CB group, 4.3% (6/140) and 1.4% (2/140) of csPCa cases were detected with targeted-only and systematic-only biopsy cores, respectively. In the CB group, 22/140 (15.7%) patients were diagnosed with ncsPCa compared to 33/140 (23.6%) in the SOB group (RR = 0.67, 95% CI: 0.41-1.08, p = 0.1). When comparing SOB to CB (ATT), the marginal OR was 0.56 (95% CI: 0.38-0.82, p = 0.003) for the diagnosis of csPCa and 0.75 (95% CI: 0.47-1.05, p = 0.085) for the diagnosis of overall cancer (≥ISUP 1). CONCLUSION: The CB approach was superior to the SOB approach in detecting csPCa, while no additional detection of ncsPCa was seen. Our results support the application of mpMRI for biopsy-naïve patients with suspicions of prostate cancer.

Development and evaluation of the MiCheck® Prostate test for clinically significant prostate cancer.

BACKGROUND: There is a clinical need to identify patients with an elevated PSA who would benefit from prostate biopsy due to the presence of clinically significant prostate cancer (CSCaP). We have previously reported the development of the MiCheck® Test for clinically significant prostate cancer. Here, we report MiCheck's further development and incorporation of the Roche Cobas standard clinical chemistry analyzer. OBJECTIVES: To further develop and adapt the MiCheck® Prostate test so it can be performed using a standard clinical chemistry analyzer and characterize its performance using the MiCheck-01 clinical trial sample set. DESIGN, SETTINGS, AND PARTICIPANTS: About 358 patient samples from the MiCheck-01 US clinical trial were used for the development of the MiCheck® Prostate test. These consisted of 46 controls, 137 non-CaP, 62 non-CSCaP, and 113 CSCaP. METHODS: Serum analyte concentrations for cellular growth factors were determined using custom-made Luminex-based R&D Systems multi-analyte kits. Analytes that can also be measured using standard chemistry analyzers were examined for their ability to contribute to an algorithm with high sensitivity for the detection of clinically significant prostate cancer. Samples were then re-measured using a Roche Cobas analyzer for development of the final algorithm. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression modeling with Monte Carlo cross-validation was used to identify Human Epidydimal Protein 4 (HE4) as an analyte able to significantly improve the algorithm specificity at 95% sensitivity. A final model was developed using analyte measurements from the Cobas analzyer. RESULTS: The MiCheck® logistic regression model was developed and consisted of PSA, %free PSA, DRE, and HE4. The model differentiated clinically significant cancer from no cancer or not-clinically significant cancer with AUC of 0.85, sensitivity of 95%, and specificity of 50%. Applying the MiCheck® test to all evaluable 358 patients from the MiCheck-01 study demonstrated that up to 50% of unnecessary biopsies could be avoided while delaying diagnosis of only 5.3% of Gleason Score (GS) ≥3+4 cancers, 1.8% of GS≥4+3 cancers and no cancers of GS 8 to 10. CONCLUSIONS: The MiCheck® Prostate test identifies clinically significant prostate cancer with high sensitivity and negative predictive value (NPV). It can be performed in a clinical laboratory using a Roche Cobas clinical chemistry analyzer. The MiCheck® Prostate test could assist in reducing unnecessary prostate biopsies with a marginal number of patients experiencing a delayed diagnosis.

Current magnetic resonance imaging-based diagnostic strategies for prostate cancer.

Recent developments in multiparametric MRI and MRI-targeted biopsy have made it possible to detect clinically significant cancers more accurately and efficiently than ever before. Furthermore, software that enables easy MRI/US image fusion has been developed and is already available on the market, and this has provided a tailwind for the spread of MRI-based prostate cancer diagnostic strategies. Such precise diagnosis of prostate cancer localization is essential for highly accurate focal therapy. In addition, a recent large-scale study applying MRI to community screening for prostate cancer has reported its usefulness. By contrast, concerns about overdiagnosis and overtreatment, the existence of inter-reader variability in MRI diagnosis, and issues with current MRI-targeted biopsy have emerged. In this article, we review the development of multiparametric MRI and MRI-targeted biopsy to date and the current issues and discuss future directions.

Diagnostic Performance and Clinical Impact of PSMA PET/CT versus mpMRI in Patients with a High Suspicion of Prostate Cancer and Previously Negative Biopsy: A Prospective Trial (PROSPET-BX).

BACKGROUND: This prospective single-arm study is designed to compare in parallel 68Ga-PSMA PET/TRUS (transrectal or transperineal) fusion biopsy ("experimental test") with multiparametric MRI (mpMRI)/TRUS fusion prostate biopsy ("standard test") in men with a high suspicion of prostate cancer (PCa) after at least one negative biopsy. The primary objective was to evaluate the diagnostic performance of 68Ga-PSMA PET/TRUS fusion prostate biopsy in comparison to mpMRI/TRUS fusion prostate biopsy analyzed in parallel. Secondarily, we aimed to determine the relationship between the "experimental test" and the histopathological characteristics of the specimen, along with the clinical utility of the "experimental test" compared to the "standard test." SUMMARY: To test the superiority of 68Ga-PSMA PET/CT compared to mpMRI, we will enroll a minimum cohort of 128 patients. Inclusion criteria comprise: age >18 years; blood PSA level >4.0 ng/mL; free-to-total PSA ratio <20%; progressive rise of PSA levels in two consecutive blood samples despite antibiotics; serum blood tests suspicious for PCa; at least one previous negative biopsy; ASAP and/or high-grade PIN; negative digital rectal examination. All eligible patients will undergo 68Ga-PSMA PET/CT and mpMRI scans within 1 month's distance from each other, followed by biopsy session to be completed within 1 month's distance. Targeted TRUS fusion needle biopsy will be performed for all lesions detected with PET and mpMRI. The total duration of the study is 36 months. KEY MESSAGES: By comparing the "experimental test" and the "standard test" in parallel, we will be able to determine the superior diagnostic performance of 68Ga-PSMA PET/CT over mpMRI in detecting PCa, and in particular clinically significant PCa, in the specific cohort of patients with a high suspicion of PCa who are candidates to re-biopsy. The clinical impact of the "experimental test" will be subsequently analyzed in terms of the number of prostate biopsies that could be spared, time-consuming, patient friendliness, and cost-effectiveness.

Molecular Biomarkers for the Detection of Clinically Significant Prostate Cancer: A Systematic Review and Meta-analysis.

Context: Prostate cancer (PCa) is the second most common type of cancer in men. Individualized risk stratification is crucial to adjust decision-making. A variety of molecular biomarkers have been developed in order to identify patients at risk of clinically significant PCa (csPCa) defined by the most common PCa risk stratification systems. Objective: The present study aims to examine the effectiveness (diagnostic accuracy) of blood or urine-based PCa biomarkers to identify patients at high risk of csPCa. Evidence acquisition: A systematic review of the literature was conducted. Medline and EMBASE were searched from inception to March 2021. Randomized or nonrandomized clinical trials, and cohort and case-control studies were eligible for inclusion. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Pooled estimates of sensitivity, specificity, and area under the curve were obtained. Evidence synthesis: Sixty-five studies (N = 34 287) were included. Not all studies included prostate-specific antigen-selected patients. The pooled data showed that the Prostate Health Index (PHI), with any cutoff point between 15 and 30, had sensitivity of 0.95-1.00 and specificity of 0.14-0.33 for csPCa detection. The pooled estimates for SelectMDx test sensitivity and specificity were 0.84 and 0.49, respectively. Conclusions: The PHI test has a high diagnostic accuracy rate for csPCa detection, and its incorporation in the diagnostic process could reduce unnecessary biopsies. However, there is a lack of evidence on patient-important outcomes and thus more research is needed. Patient summary: It has been possible to verify that the application of biomarkers could help detect prostate cancer (PCa) patients with a higher risk of poorer evolution. The Prostate Health Index shows an ability to identify 95-100 for every 100 patients suffering from clinically significant PCa who take the test, preventing unnecessary biopsies in 14-33% of men without PCa or insignificant PCa.

The Role of [68Ga]PSMA PET/CT for Clinical Suspicion of Prostate Cancer in Patients with or without Previous Negative Biopsy: A Systematic Review.

The purpose of the study is to systematically evaluate the evidence regarding the role of [68Ga]PSMA PET/CT for clinical suspicions of prostate cancer in patients with or without previous negative biopsy. We performed a critical review of PubMed and Web of Science according to the PRISMA statement. Eighteen publications were selected for inclusion in this analysis. QUADAS-2 evaluation was adopted for quality analyses. [68Ga]PSMA-11 was the radiotracer of choice in 15 studies, while [68Ga]PSMA-617 was used in another 3. In 8 articles, there was a direct comparison with mpMRI. The total number of patients included was 1379, ranging from 15 to 291, with a median age of 64 years (range: 42-90). The median baseline PSA value was 12.9 ng/mL, ranging from 0.85 to 4156 ng/mL. Some studies evaluated the PSMA uptake comparing the SUVmax of suspicious lesions with the SUVmax of the normal biodistribution to find out optimal cut-off points. In addition, some studies suggested a significant association between PSA levels, PSA density, and [68Ga]PSMA PET/CT finding. [68Ga]PSMA PET/CT seems to be more accurate in identifying primary prostate cancer with PSA values between 4 and 20 ng/mL than mpMRI. Moreover, in some trials, the combination of PSMA PET/CT and MRI improved the NPV in the detection of clinically significant prostate cancer (csPCa) than MRI alone. Our findings are limited by the small numbers of studies and patient heterogeneity. [68Ga]PSMA PET/CT is a promising technique in patients with clinical suspicion of PCa and precedent negative biopsy or contraindications to MRI. Furthermore, its use combined with MRI improves sensitivity for csPCa detection and can avoid unnecessary biopsies.

A Prospective Study and Single-Center Experience: Effectivity of Fusion Prostate Biopsy in Biopsy-Naïve Patients.

Objective Fusion prostate biopsy (FPB) has become a popular technique in biopsy-naïve patients, though not accepted as a standard approach (yet). In this study, we aimed to present the clinical outcomes of biopsy-naïve patients who underwent FPB. Material and methods The study included 400 biopsy-naïve patients aged 45-75 years who had a prostate-specific antigen (PSA) level of 2-10 ng/ml and were detected with a Prostate Imaging-Reporting and Data System (PIRADS) ≥3 lesion on multiparametric prostate magnetic resonance imaging (mpMRI)-guided FPB. A combined biopsy (CB) was performed in each patient, in which 2-4 cores were obtained for suspicious lesions by targeted biopsy (TB) and then 12-core standard prostate biopsy (SPB) was conducted in the same session. Cancer detection rates, clinically significant prostate cancer (csPCa) detection rates, histological upgrading rates, and false negative rates were determined. Results The 400 patients had a mean age of 62.01±7.00 years and a mean PSA value of 6.84±1.87 ng/ml. Overall PCa detection rate was 50% (200/400). The csPCa detection rates for TB, SPB, and CB were 25.0%, 31.8%, and 44.0%, respectively (p<0.001). In PIRADS 3, 4, and 5 lesions, CB had a csPCa detection rate of 29.2%, 54%, and 64.8%, respectively (p<0.001). The ratio of false negativity was significantly higher for TB compared to SPB (43.2% vs. 27.8%, p=0.003), whereas no significant difference was found between these two techniques with regard to upgrading rates although TB had a higher rate (19.6% vs. 13.7%, p=0.144). Conclusion FPB, a combined approach involving TB and SPB, was revealed as the most successful technique in biopsy-naïve patients with PSA<10 ng/ml due to its high cancer detection rates and low false negative rates.

Serum and urine biomarkers for detecting clinically significant prostate cancer.

Since the "prostate-specific antigen (PSA) era," we have seen an increase in unnecessary biopsies, which has ultimately lead to an overtreatment of low-risk cancers. Given the limitations of prostate-specific antigen and the invasive nature of prostate biopsy several serum and urinary biomarkers have been developed. In this paper, we provide a comprehensive review of the available biomarkers for the detection clinically significant prostate cancer namely PHI, 4Kscore, PCA3, MiPS, SelectMDx, ExosomeDX. Current literature suggests that these biomarkers can improve detection of clinically significant prostate cancer reducing overtreatment and making treatment strategies more cost-effective. Nevertheless, large prospective studies with head-to-head-comparisons of the available biomarkers are necessary to fully assess the potential of incorporating biomarkers in routine clinical practice.

Magnetic resonance imaging/transrectal ultrasonography fusion targeted prostate biopsy finds more significant prostate cancer in biopsy-naïve Japanese men compared with the standard biopsy.

OBJECTIVE: To assess the clinical benefits of magnetic resonance imaging/transrectal ultrasound fusion-targeted biopsy for biopsy-naïve Japanese men. METHODS: Between February 2017 and August 2018, 131 biopsy-naïve men who underwent targeted biopsy together with 10-core systematic biopsy at Hiroshima University Hospital were retrospectively investigated. Multiparametric magnetic resonance imaging findings were reported based on Prostate Imaging Reporting and Data System version 2. RESULTS: The overall cancer detection rates per patient were 69.5% in systematic biopsy + targeted biopsy cores, 61.1% in systematic biopsy cores and 61.1% in targeted biopsy cores. The detection rates for clinically significant prostate cancer were 43.5% in targeted biopsy cores and 35.9% in systematic biopsy cores (P = 0.04), whereas the detection rates for clinically insignificant prostate cancer were 17.6% and 25.2% respectively (P = 0.04). Lesions in the peripheral zone were diagnosed more with clinically significant prostate cancer (54.8% vs 20.7%, P < 0.001) and International Society of Urological Pathology grade (3.2 vs 2.7, P = 0.02) than that in the inner gland. Just 4.2% (3/71) of Prostate Imaging Reporting and Data System category 2 and 3 lesions in the middle or base of the inner gland were found to have clinically significant prostate cancer. The cancer detection rate per core was 42.3% in targeted biopsy cores, whereas it was 17.9% in systematic biopsy cores (P < 0.001). CONCLUSIONS: Targeted biopsy is able to improve the diagnostic accuracy of biopsy in detection of clinically significant prostate cancer by reducing the number of clinically insignificant prostate cancer detections compared with 10-core systematic biopsy in biopsy-naïve Japanese men. In addition, the present findings suggest that patients with Prostate Imaging Reporting and Data System category 2 or 3 lesions at the middle or base of the inner gland might avoid biopsies.

Is Prostate Imaging Reporting and Data System Version 2 Sufficiently Discovering Clinically Significant Prostate Cancer? Per-Lesion Radiology-Pathology Correlation Study.

OBJECTIVE: The objective of our study was to evaluate the performance of multiparametric MRI with Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) for detecting prostate cancer (PCA) and clinically significant PCA through this per-lesion one-to-one correlation study between pathologically proven lesions and MRI-visible lesions. MATERIALS AND METHODS: A total of 93 PCA lesions from 44 patients who underwent radical prostatectomy were included in this retrospective study. Two radiologists scored every visible lesion with a PI-RADSv2 score of 3, 4, or 5 in each patient's multiparametric MRI examination using PI-RADSv2. A per-lesion one-to-one correlation between MRI-visible lesions and pathologically confirmed PCA lesions was conducted during regular radiology-pathology meetings at our center. The detection rates of clinically significant PCA and the proportions of clinically significant PCAs from MRI-visible and MRI-invisible PCAs were calculated. The performance of PI-RADSv2 for detecting clinically significant PCA was evaluated using the positive predictive value (PPV), negative predictive value (NPV), and area under the ROC curve (AUC) value. RESULTS: Using a PI-RADSv2 score of 3, 4, or 5 as an MRI-visible lesion, 46.88% of clinically significant PCA lesions were detected. The PPV, NPV, and AUC were 96.77%, 45.16%, and 0.72, respectively. Tumor volume and secondary Gleason grade showed a statistically significant difference between MRI-visible and MRI-invisible clinically significant PCAs. CONCLUSION: Multiparametric MRI with PI-RADSv2 missed a considerable number of clinically significant PCA lesions in this per-lesion analysis, causing a relatively low NPV and diagnostic performance compared with previous per-patient studies. However, the high PPV indicates that multiparametric MRI with PI-RADSv2 may be useful for follow-up of active surveillance and planning focal therapy.

Novel application of three-dimensional shear wave elastography in the detection of clinically significant prostate cancer.

The present study evaluated three-dimensional shear wave elastography (3D SWE) in the detection of clinically significant prostate cancer. Clinically significant prostate cancer was defined by a minimum of one biopsy core with a Gleason score of 3+4 or 6 with a maximum cancer core length >4 mm. Patients with serum prostate-specific antigen levels of 4.0-20.0 ng/ml who were suspected of having prostate cancer from multi-parametric magnetic resonance imaging (mpMRI) were prospectively recruited. The 3D SWE was performed pre-biopsy, after which patients underwent MRI-transrectal ultrasound image-guided targeted biopsies for cancer-suspicious lesions and 12-core systematic biopsies. The pathological biopsy results were compared with the mpMRI and 3D SWE images. A total of 12 patients who were suspected of having significant cancer on mpMRI were included. The median pre-biopsy PSA value was 5.65 ng/ml. Of the 12 patients, 10 patients were diagnosed as having prostate cancer. In the targeted biopsy lesions, there was a significant difference in Young's modulus between the cancer-detected area (median 64.1 kPa, n=20) and undetected area (median 30.8 kPa, n=8; P<0.0001). On evaluation of receiver operating characteristics, a cut-off value of the Young's modulus of 41.0 kPa was used for the detection of clinically significant cancer, with which the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of cancer detection were 58, 97, 86 and 87%, respectively. When combining this cut-off tissue elasticity value with Prostate Imaging Reporting and Data System (PI-RADS) scores, the sensitivity, specificity, positive predictive value and negative predictive value of cancer detection were improved to 70, 98, 91 and 92%, respectively. In the cancer-detected lesions, a significant correlation was identified between the tissue elasticity value of the lesions and Gleason score (r=0.898, P<0.0001). In conclusion, PI-RADS combined with measurement of Young's modulus by 3D SWE may improve the diagnosis of clinically significant prostate cancer.

Future Perspectives and Challenges of Prostate MR Imaging.

MR imaging is an important part of prostate cancer diagnosis. Variations in quality and skill in general practice mean results are not as impressive as they were in academic centers. This observation provides an impetus to improve the method. Improved quality assurance will likely result in better outcomes. Improved characterization of clinically significant prostate cancer may assist in making MR imaging more useful. Improved methods of registering MR imaging with transrectal ultrasound imaging and robotic arms controlling the biopsy can reduce the impact of inexperienced operators and make the entire system of MR imaging-guided biopsies more robust.

When no treatment is the best treatment: Active surveillance strategies for low risk prostate cancers.

Although the incidence of prostate cancer is rising due to PSA screening and increased life expectancy, the metastatic potential of low-grade, organ-confined disease remains low. An increasing number of studies suggest that radical treatment in such cases confers little or no survival benefit at a significant cost to morbidity. Active surveillance is a promising management approach of such low-risk cancers: eligible patients are selected based on clinical and pathological findings at diagnosis and are regularly monitored with digital rectal examinations, PSA testing and biopsies. Treatment, however, is deferred until and unless there is evidence of disease progression. This is a key difference from watchful waiting, where treatment is avoided until and unless there are symptoms. The purpose of this work is to review the rationale and evidence behind active surveillance and to offer an overview of current active surveillance strategies and outcomes.

PI-RADS Version 2: Detection of Clinically Significant Cancer in Patients With Biopsy Gleason Score 6 Prostate Cancer.

OBJECTIVE: The purpose of this study was to analyze the utility of the Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) in the detection of a clinically significant cancers in patients with prostate cancers with a biopsy Gleason score of 6. MATERIALS AND METHODS: A group of 182 consecutively registered patients with biopsy-proven prostate cancer with a Gleason score of 6 underwent MRI and radical prostatectomy. Clinically significant cancer was surgically defined as Gleason score of 7 or greater, tumor volume of 0.5 cm3 or greater, or tumor category T3 or greater. Clinical parameters (prostate-specific antigen level, greatest percentage of biopsy core, and percentage of positive cores) and the PI-RADSv2 ratings by three independent readers (experienced readers 1 and 2, inexperienced reader 3) were investigated. Cutoffs and the diagnostic performance of PI-RADSv2 for clinically significant cancer were analyzed. RESULTS: Clinically significant cancer was found in 87.4% (159/182) of patients. The cutoff PI-RADSv2 score for clinically significant cancer was 4 for readers 1 and 2 and 5 for reader 3. The AUCs were 0.829 and 0.853 for readers 1 and 2 (p < 0.001) and 0.602 for reader 3 (p = 0.067). For reader 1, sensitivity was 89.9% (143/159); specificity, 69.6% (16/23); positive predictive value, 95.3% (143/150); negative predictive value, 50.0% (16/32); and accuracy, 87.4% (159/182). The corresponding values for reader 2 were 81.1% (129/159), 82.6% (19/23), 97.0% (129/133), 38.8% (19/49), and 81.3% (148/182). For the experienced readers, 66.7-81.3% of patients with false-negative results had clinically significant cancers with tumor volume less than 1 cm3. CONCLUSION: PI-RADSv2 may help experienced readers identify clinically significant prostate cancers in patients with a biopsy Gleason score of 6. However, some small (< 1 cm3) clinically significant cancers can be missed when PI-RADSv2 is used.